The anthracycline glycosides are antibiotics in which a tetrahydronaphthacene chromophore is linked to a sugar, most commonly a basic sugar. Representative anthracycline glycoside antibiotics include
doxorubicin PA0 daunorubicin PA0 daunorubicinol PA0 doxorubicinol
and pharmaceutically acceptable analogues, derivatives and salts thereof.
Anthracycline glycosides, such as doxorubicin HCl (Adriamycin, a product of U.S. Pat. No. 3,590,028) and daunorubicin (U.S. Pat. No. 4,012,284) and pharmaceutically acceptable analogues, derivatives and salts thereof, are also known oncolytic agents. Representative analogues are described in U.S. Pat. No. 3,686,136 and K. Yamamoto et al., J. Med. Chem. 15, 872 (1973); German Pat. Nos. 2,327,211; 2,557,537; and 1,920,198; E. Bachman et al., Agents and Actions 5/4, 383 (1975); P. Chandra, Cancer Chemother. Rep. 6, 115 (1975); F. Arcamone et al., id. at 123; and G. Zbinden et al., Cancer Chemother. Rep. 4, 707 (1975), the disclosures of which are incorporated herein by reference.
Overall usefulness of the anthracycline glycosides as antibiotics and oncolytic agents is severely restricted because of inherent treatment-limiting and potentially lethal cardiotoxicity. The cardiotoxic effects of doxorubicin HCl (Adriamycin) and daunorubicin have been documented (U.S. Pat. No. 4,138,480). Cumulative myocardial damage has been correlated with Adriamycin doses in excess of 500 mg/m.sup.2, or less in patients with prior medastinal irradiation, and takes the form of refractory congestive heart failure. Electron microscopic studies of the heart tissue in such cases have demonstrated a striking degeneration of myofibrills and mitochondrial distortion as well as a decrease in cardiac myocytes, Lefrak, E. A., Pitha, J., Rosenheim, S., O'Bryan, R. M., Burgess, M. A., Gottlieb, J. A.: Adriamycin (NSC-123127) Cardiomyopathy. Cancer Chemother. Rep. 6:203-208 (1975). Pharmacokinetic studies have shown that Adriamycin (doxorubicin HCl) is taken up avidly and preferentially by heart muscle, Yesair, D. W., Schwartzbach, E., Shuck, D., Denine, E. P., Asbell, M. A.: Comparative pharmacokinetics of Daunomycin and Adriamycin in several animal species. Cancer Research 32:1177-1183 (1972). It is known that administration of Adriamycin (doxorubicin HCl) causes the occurrence of cardiac toxicity at doses lower than recommended cumulative limit and therefore it is not recommended to start the use of doxorubicin HCl in such cases. Also, starting treatment is contraindicated in cases where there has been previous treatment with complete cumulative doses of Adriamycin and/or daunorubicin.
The present invention is directed to a delivery system which will selectively reduce the uptake of anthracycline glycoside drugs, such as doxorubicin HCl, in cardiac tissue, while preserving the drug's antibiotic and antitumor activity.